Optimizing transcutaneous vagus nerve stimulation parameters for sleep and autonomic function in veterans with posttraumatic stress disorder with or without mild traumatic brain injury

Abstract Study Objectives Transcutaneous vagus nerve stimulation (tVNS) has emerged as a potential therapeutic intervention for posttraumatic stress disorder (PTSD), yet optimal stimulation parameters remain undetermined. This study aimed to identify the most effective tVNS parameters for enhancing sleep architecture and autonomic function in veterans with PTSD. Methods Twenty-one veterans with PTSD underwent three nights of polysomnography with tVNS administered for 1 hour at lights out. Nine combinations of pulse width (100μs, 500μs), frequency (10, 20, 25 Hz), and intensity threshold (80% discomfort, 100% sensory, 200% sensory) were tested against sham stimulation. Primary outcomes were percentage of slow wave (N3) sleep, next-day resting respiratory sinus arrhythmia (RSA), and electrodermal activity during an emotionally modulated startle task. Results The parameter combination of 20Hz, 100μs pulse width, and 80% discomfort threshold was associated with the most optimal outcomes across both intent-to-treat and per protocol analyses. This combination significantly improved slow wave sleep percentage and next-day startle response compared to sham, but not next-day resting RSA. The 80% discomfort threshold setting outperformed other intensity thresholds. While frequency and pulse width combinations did not significantly differ, 20 Hz, 100 μs allowed for higher stimulation intensity due to greater tolerability. Conclusions A single session of tVNS using 20 Hz, 100 μs, and 80% discomfort threshold parameters improved sleep and autonomic features of PTSD compared to sham stimulation. This combination may be preferred due to allowing higher stimulation intensity while maintaining tolerability. These findings further our understanding of the neurophysiological effects of different tVNS parameter settings and may inform parameter selection in future clinical trials of tVNS. Clinical Trial Information Non-invasive Nerve Stimulation and Sleep (NINS), NCT04021537; https://clinicaltrials.gov/study/NCT04021537